a surprising cause of chronic cough

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 373;6 nejm.org August 6, 2015 561

Clinical Problem-Solving

A 63-year-old nonsmoking white man presented to the clinic with a 2-year history of cough. The cough was dry, and it was worse at night. The cough had begun after an upper respiratory tract infection and a trip to South America. The patient was pre-scribed antibiotics by a family physician but had no improvement; he was then given a combination inhaler (salmeterol and fluticasone) and had minimal improvement.

This patient has chronic cough, which is defined as a cough lasting more than 8 weeks. In a nonsmoker, the most common causes are the upper-airway cough syndrome (allergic, nonallergic, or infectious), asthma, and gastroesophageal re-flux disease (GERD). This patient has features suggestive of GERD or the upper-airway cough syndrome after an upper respiratory tract infection. Although the long duration of cough may suggest mild asthma, this condition should have improved substantially with the correct use of a combination inhaler.

The patient’s medical history included at least 5 years of intermittent arthralgias and myalgias and a 2-year history of night sweats (now resolved) before this presentation. The arthralgias occurred in his neck, shoulders, wrists, hands, hips, and ankles; episodes would last 2 weeks on average, followed by complete recovery. He was as-sessed by a rheumatologist during the first 2 years after the onset of these symptoms and had negative results on tests for antinuclear antibody (rheumatoid factor, ex-tractable nuclear antigens, and anti–cyclic citrullinated peptide antibodies) and HLA-B27. A tuberculin skin test, chest radiography, and ultrasonography of the ab-domen were also negative. Additional medical history included pitting edema in the lower limbs bilaterally for the past 2 years (attributed to venous stasis), for which the patient used compression stockings. There was no other clinically significant medi-cal history. The patient had never smoked, and he drank minimal amounts of alcohol. He had no pets. His only medications were the inhaler and ibuprofen (as needed).

Given the absence of allergies or history of rhinitis, the upper-airway cough syn-drome is less likely. Ibuprofen may be a risk factor for bronchospasm or nasal congestion in a patient with asthma and rhinosinusitis with nasal polyps. This patient’s history of night sweats and arthralgias may relate to his current presen-tation, but this remains unclear. He does not have additional findings to suggest sarcoidosis, such as a history of erythema nodosum or hilar adenopathy.

Asthma or GERD remains a likely cause of his cough, although imaging is warranted to assess for parenchymal lung disease. If the patient has asthma, it

From the Department of Medicine, Uni-versity of British Columbia, Vancouver, Canada. Address reprint requests to Dr. Damaraju at 5288 Melbourne St., Apt. 1702, Vancouver, BC V5R 6E6, Canada, or at deepti . damaraju@ gmail . com.

N Engl J Med 2015;373:561-6.DOI: 10.1056/NEJMcps1303787Copyright © 2015 Massachusetts Medical Society.

Caren G. Solomon, M.D., M.P.H., Editor

A Surprising Cause of Chronic CoughDeepti Damaraju, M.D., Ted Steiner, M.D., John Wade, M.D., Kenneth Gin, M.D.,

and J. Mark FitzGerald, M.B., M.D.

In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information, sharing his or her reasoning with the reader (regular type).

The authors’ commentary follows.

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may be incompletely responsive to inhaled med-ication for several reasons (incorrect inhaler tech-nique, inadequate adherence to therapy, poor avoidance of triggers, the presence of vocal-cord dysfunction, or untreated nasal symptoms). Spirometry and chest imaging should be ordered to assess for parenchymal lung disease.

Spirometry, including the flow-volume loop, was normal. A methacholine challenge was negative; with sequential inhalations up to 16 mg per mil-liliter, the fall in the forced expiratory volume in 1 second (FEV1) was 9% (final FEV1, 3.60 liters, which was 89% of the predicted level). A comput-ed tomographic (CT) scan of the chest showed mild bronchiectasis and no other clinically signifi-cant abnormality.

The normal flow-volume loop rules out clinical-ly significant fixed obstruction (from vocal-cord dysfunction or a mass). A methacholine chal-lenge in this context, with the use of a cutoff value of 8 to 16 mg per milliliter for the concen-tration of methacholine required to reduce the FEV1 by 20%, has a high negative predictive value; the negative results (i.e., fall in FEV1 of <20% with maximal challenge) makes a diagno-sis of asthma highly unlikely.

In this patient, GERD appears to be the next most likely cause. A 24-hour pH monitor could be considered. Alternatively, a trial of therapy with a proton-pump inhibitor would be reasonable.

The patient declined pH monitoring but agreed to try a proton-pump inhibitor. However, he did not return for follow-up.

Three years later, he returned and reported new symptoms that had been present for 6 months. These symptoms began with intense gas pain, bloating, and small-volume diarrhea; the diarrhea decreased spontaneously over a period of 6 weeks, and the gas and bloating decreased after several months, which he attributed to increased dietary fiber intake. Two months after the initial develop-ment of gastrointestinal symptoms, he had sud-den severe leg pain and difficulty walking. Al-though the severe pain resolved within days, he continued to have myalgias and arthralgias as well as intermittent cough, which he noted had not abated with the use of a proton-pump inhibitor.

One month after the episode of leg pain, a severe

headache developed that lasted for 2 days, and the patient had transient binocular vision loss, for which he was evaluated at an outside emergency department. He had an elevated C-reactive protein level (44.7 mg per liter; normal value, <3.0 mg per liter) and erythrocyte sedimentation rate (69 mm per hour; normal value, <25 mm per hour). His hemoglobin level was 13.5 g per deciliter, and the white-cell count was 8.7×103 per cubic milli-meter (neutrophils 7.3×103 per cubic millimeter, lymphocytes 0.9×103 per cubic millimeter, mono-cytes 0.3×103 per cubic millimeter, and eosinophils 0.2×103 per cubic millimeter). Electrolyte and cre-atinine levels were normal. A CT scan of the head was normal. A presumptive diagnosis of temporal arteritis and polymyalgia rheumatica was made. The patient began taking prednisone (at a dose of 60 mg daily) and was referred to a rheumatologist.

The headache resolved in 2 days, and the visual loss did not recur. A temporal-artery biopsy sev-eral weeks later was negative for vasculitis. Given the rapid resolution of his neurologic symptoms while he was taking prednisone, the patient con-tinued taking this medication and was followed for several months. He noted a marked reduction in his chronic arthralgias and myalgias and slight abatement of his cough and long-standing pe-ripheral edema. With tapering to a dose of 10 mg per day, however, his cough and arthralgias wors-ened (with no recurrence of neurologic symp-toms). He was again referred to his original pul-monologist.

Patients with giant-cell arteritis can have a non-productive cough that is caused by vasculitic involvement of airways. This patient’s cough worsened as prednisone was tapered, which sug-gested a possible underlying inflammatory cause (such as eosinophilic bronchitis, a pulmonary vas-culitis, or, less likely, an interstitial pneumonitis). False negative results on biopsies may occur in patients with temporal arteritis. In cases in which the biopsy is negative, the clinical suspicion for temporal arteritis must be weighed against the risks of glucocorticoid use (e.g., worsening of oc-cult infection, impaired glucose tolerance, bone loss, and avascular necrosis). Alternative diagno-ses should continue to be considered, with the understanding that patients without temporal arteritis may also report improvement while tak-ing prednisone.





A CT scan of the chest and abdomen showed mild interstitial pulmonary edema and small bilateral pleural effusions. The main pulmonary artery was enlarged at 30.9 mm in diameter, and there was a small pericardial effusion. There was exten-sive abdominal lymphadenopathy, which was considered to be a potential marker of lymphoma, as well as a region of poorly distended proximal jejunum that appeared to be thickened (Fig. 1).

The findings on the CT scan of the abdomen may suggest a lymphoproliferative disease or other cancer involving the jejunum. Lymphadenopathy may also be explained by infection, including tuberculosis; the prior negative tuberculin skin test does not rule out tuberculosis, because this testing is often negative in patients with dis-seminated tuberculosis. The patient should be examined for peripheral adenopathy to identify nodes that would be amenable to biopsy. The findings on the CT scan of the chest may indi-cate heart failure and warrant further evaluation, including assessment for cardiomyopathy or valvular disease.

The patient had no palpable peripheral adenopa-thy and, given a high clinical suspicion of lym-

phoma, was referred for exploratory laparotomy and excisional lymph-node biopsy. Microbiologic testing of the sample revealed gram-positive ba-cilli, which prompted the laboratory to investigate for possible Whipple’s disease. Direct 16S gene sequencing detected Tropheryma whipplei DNA. Pathological findings from the lymph-node biopsy showed granulomatous inflammation with nu-merous foamy histiocytes (Fig. 2). Organisms that were positive on periodic acid–Schiff staining were present and had morphologic features con-sistent with those of T. whipplei. Blood cultures were negative.

Whipple’s disease provides a unifying diagnosis for this patient’s presentation, including the chronic arthropathy, cough, lymphadenopathy, and lymphopenia. The diagnosis could have been made by less invasive means (i.e., small-bowel endoscopy) had it been suspected preop-eratively. The absence of chronic diarrhea in this case is atypical for Whipple’s disease.

The infectious disease service was consulted, and it was recommended that the patient receive intra-venous ceftriaxone for 2 weeks, followed by oral trimethoprim–sulfamethoxazole at a dose of one

Figure 1. Computed Tomographic Scan of the Abdomen.

Coronal sections show enlarged and borderline mesenteric lymph nodes, with indicated measurements.

9.8 mm

13.0 mm

16.1 mm8.2 mm

10.7 mm





double-strength tablet (160 mg of trimethoprim and 800 mg of sulfamethoxazole) twice daily. The prednisone was tapered and subsequently discon-tinued. At follow-up 2 weeks later, the patient was found to have a systolic murmur, which had not been noted previously. An echocardiogram showed a mobile mass measuring 7 mm in length by 6 mm in width on the left ventricular surface of a bicus-pid aortic valve, with mild aortic stenosis and moderate aortic insufficiency; systolic pulmo-nary-artery pressures could not be estimated (Fig. 3 and Video 1). He had no fevers, cardiac symptoms, or embolic phenomena of endocardi-tis. Three blood cultures were negative.

The patient was referred for assessment to a cardiologist, who considered the vegetation to be a likely complication of Whipple’s disease and

Videos showing echocardiograms

are available at NEJM.org

Figure 2. Pathological Findings.

The low-power photomicrograph in Panel A shows a markedly abnormal intraabdominal lymph node in which the normal architecture has been replaced by numerous macrophages, many of which are foamy, and occasional giant cells (hematoxylin and eosin). The high-power photomicrograph in Panel B shows foamy macrophages with granular eosinophilic cytoplasm (hematoxylin and eosin). Panel C (periodic acid–Schiff stain) and Panel D (Warthin–Starry silver stain) show numerous intracytoplasmic organisms, with morphologic features consistent with those of Troph-eryma whipplei.

A B

DC

Figure 3. Transesophageal Echocardiogram.

A mobile vegetative mass is seen on the noncoronary cusp of the aortic valve.

Mitral valve

Vegetation

Left ventricle

Left atrium

Aorta

Aortic valve





who recommended follow-up with antibiotic ther-apy. The patient reported resolution of his cough, peripheral edema, arthralgias, myalgias, and fa-tigue in the 2 months after the initiation of anti-biotic therapy. Serial echocardiograms showed resolution of the vegetation by the sixth month of therapy, with stable valvular regurgitation (Fig. 4 and Video 2).

It is possible that the transient vision loss earlier may have been embolic in nature in association with endocarditis (although vision loss in this context would be much less likely to be bilateral than unilateral). The resolution of the patient’s cough and other symptoms, as well as the valvu-lar vegetation, with antibiotic therapy supports the conclusion that these were attributable to Whipple’s disease.

Commen ta r y

Chronic cough lasting more than 8 weeks is common and most often caused by broncho-spasm, GERD, eosinophilic bronchitis, or the upper-airway cough syndrome (postnasal drip).1,2 These were not the culprits in our patient, and the presence of other symptoms (edema, arthral-gias, myalgias, night sweats, diarrhea, and head-ache) suggested that a systemic condition was responsible for his cough and other symptoms.

In this patient, Whipple’s disease was the underlying cause. Whipple’s disease is a chronic infectious disease that affects multiple organ systems; it is a rare disease, with a reported an-nual incidence of less than 1 case per 1,000,000 people.3 It is caused by T. whipplei, a ubiquitous environmental organism. T. whipplei is thought to be acquired by fecal–oral transmission and is found in sewage-plant effluxes.4 The organism is dependent on host cells for growth and is one of the slowest-growing pathogenic bacteria in humans, with a generation time of 18 days.5 The disease appears to occur more frequently in per-sons of European ancestry than in persons of other ancestries and more frequently in men than in women (male:female ratio, 4:1). It most often manifests in middle age, although cases occur across the age spectrum.6

Whipple’s disease has a broad spectrum of symptoms and signs; typical manifestations (and their frequency in case series) include weight

loss (in 92% of patients), diarrhea (in 76%), ar-thralgia (in 67%), abdominal pain (in 55%), fever (in 38%), supranuclear ophthalmoplegia (in 32%), headache (in 10%), anemia (in 85%), lymphade-nopathy (in 60%), endocarditis (in 30%, and usually culture-negative), and pulmonary involve-ment (in 30 to 40%, approximately half of whom have cough).3,7 The typical presentation is a prodrome of arthritis, followed by persistent diarrhea and weight loss; arthritis can precede the gastrointestinal symptoms by many years. Neurologic manifestations may be irreversible despite treatment.

Whipple’s disease is a rare cause of chronic cough, although cough is well described in pa-tients with Whipple’s disease. In our patient, cough was a central feature. In a small case se-ries of patients who had Whipple’s disease with pulmonary involvement,7 common symptoms in-cluded dyspnea and dry cough, and findings on chest imaging included interstitial patterns, pleu-ral effusions, and mediastinal lymphadenopathy.

Whereas the diagnosis in our patient was made serendipitously owing to the lymph-node biopsy (for suspicion of lymphoma), the diag-nostic test of choice is upper gastrointestinal endoscopy with biopsies (although other tissue sites may be sampled). Macroscopic features may include pale yellow duodenal mucosa and ectatic lymph vessels. Immunohistochemical test-ing can improve the yield of histologic diagno-sis. Identification of the 16S ribosomal RNA gene

Figure 4. Transthoracic Echocardiogram.

The mobile vegetative mass resolved by the sixth month of therapy and is no longer seen on the noncor-onary cusp of the aortic valve.

Mitral valve

Left ventricle

Left atrium

Aortic valve





with the use of a polymerase-chain-reaction as-say (e.g., from feces or saliva) has high sensitivity and specificity for the organism but should not be used in isolation for diagnosis. Culture is not useful in diagnosis, because it may take months for the organism to grow and requires special techniques; serologic testing is nonspecific.3

In the absence of randomized trials, treat-ment recommendations are guided largely by case series. First-line treatment typically involves 2 weeks of ceftriaxone, followed by at least 1 year of trimethoprim–sulfamethoxazole.3 In one case series, 92% of patients receiving this regimen had a remission; the remission rate was higher than with tetracycline, especially with respect to relapse involving the central nervous system.8 For patients who have a sulfa allergy or desire only oral therapy, doxycycline plus hydroxychlo-roquine may be substituted for either or both ceftriaxone and trimethoprim–sulfamethoxazole3 (with response rates in case series similar to those reported with standard therapy). Antibi-otic treatment alone has been effective in curing culture-negative endocarditis related to Whip-ple’s disease.9,10

Whipple’s disease is notorious for masquer-ading as other inflammatory conditions (e.g., sarcoidosis), and many cases have been treated

empirically with glucocorticoids. Although some reports have described improvement in associa-tion with glucocorticoid therapy, the improve-ment was rarely sustained, and there are numer-ous reports of symptoms worsening with this medication.11

The present case shows the difficulty in rec-ognizing Whipple’s disease; its rarity and non-specific clinical features (overlapping with those of many chronic inflammatory diseases) often result in delayed diagnosis (up to 2 to 6 years after the onset of symptoms, according to some case series).10 Although Whipple’s disease is un-common, chronic infection with T. whipplei should be considered in any patient with persistent un-explained arthralgias or gastrointestinal or sys-temic symptoms.

Dr. Gin reports receiving fees for serving on advisory boards from Bayer, Forest, Boehringer Ingelheim, and Pfizer. No oth-er potential conflict of interest relevant to this article was re-ported.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

We thank the staff of the microbiology laboratory; Drs. Pat-rick Doyle and Elizabeth Bryce (University of British Columbia) and Dr. Linda Hoang (British Columbia Centre for Disease Con-trol) for making the microbiologic diagnosis of Whipple’s dis-ease with the direct 16S gene-sequencing technique; and Dr. Valerie A. White (University of British Columbia) for making the histopathological diagnosis of Whipple’s disease and providing the photomicrographs.

References1. Chung KF, Pavord ID. Prevalence, pathogenesis, and causes of chronic cough. Lancet 2008; 371: 1364-74.2. Pavord ID, Chung KF. Management of chronic cough. Lancet 2008; 371: 1375-84.3. Schneider T, Moos V, Loddenkemper C, Marth T, Fenollar F, Raoult D. Whipple’s disease: new aspects of pathogenesis and treatment. Lancet Infect Dis 2008; 8: 179-90.4. Schöniger-Hekele M, Petermann D, Weber B, Müller C. Tropheryma whipplei in the environment: survey of sewage plant influxes and sewage plant workers. Appl Environ Microbiol 2007; 73: 2033-5.

5. Raoult D, Birg ML, La Scola B, et al. Cultivation of the bacillus of Whipple’s disease. N Engl J Med 2000; 342: 620-5.6. Dobbins WI. Whipple’s disease. Spring-field, IL: Charles C Thomas, 1985.7. Urbanski G, Rivereau P, Artru L, Fenollar F, Raoult D, Puéchal X. Whipple disease revealed by lung involvement: a case report and literature review. Chest 2012; 141: 1595-8.8. Feurle GE, Marth T. An evaluation of antimicrobial treatment for Whipple’s disease: tetracycline versus trimethoprim-sulfamethoxazole. Dig Dis Sci 1994; 39: 1642-8.9. Algin A, Wegdam-Blans M, Verduin K,

Janssen H, van Dantzig JM. Tropheryma whipplei aortic valve endocarditis, cured without surgical treatment. BMC Res Notes 2012; 5: 600.10. Durand DV, Lecomte C, Cathébras P, Rousset H, Godeau P. Whipple disease: clinical review of 52 cases. Medicine (Bal-timore) 1997; 76: 170-84.11. Berent R, Auer J, Lassnig E, et al. Whipple’s disease: misdiagnosed as sar-coidosis with further tricuspid valve en-docarditis and pulmonary embolism — a case report. BMJ Case Rep 2009 bcr07.2008.0441.Copyright © 2015 Massachusetts Medical Society.

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a surprising cause of chronic cough

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